Drug Induce Liver Injury

(DILI)

Departement of Pharmacology and Clinical Pharmacy

Faculty of Pharmacy, Universitas Padjadjaran
 The Liver

• Stores vitamins, sugars, fats and other

nutrients from the food that you eat
• Builds chemicals that your body needs to stay
healthy
• Breaks down harmful substances, like alcohol
and other toxic (poisonous) chemicals
• Removes waste products from your blood
• Makes sure that your body has just the right
amount of other chemicals that it needs
Drugs and The Liver
Liver Disease

Drug-Drug
Drugs Interactions
LIVER
Drug Elimination

Drug Metabolites
(the good, the bad and the ugly)
Why Study Drugs and the Liver?

• Liver is a major biotransforming and elimination

organ
▫ Barrier and “Garbage Disposal”
• Drug-drug interactions occur in liver
▫ May increase toxicity or reduce effect
• Drugs cause liver damage
▫ Mechanism and can it be predicted?
• Liver disease in turn alters drug disposal
(remember renal disease and drug excretion?)
Hepatic Clearance of Drugs

• Liver removal of drugs/xenobiotics from

blood is termed hepatic clearance (ClH)
• Hepatic clearance is actually a very complex
process due to many steps
• Can be simplified to three factors
▫ Liver blood flow
▫ Liver intrinsic clearance
▫ Fraction of drug not bound to albumin
Hepatic Clearance of Drugs

Q (fx unbound drug) (ClINT)

ClH =
Q + (fx unbound)(ClINT)

Q = liver blood flow

ClINT = rate of ability of liver to clear blood of
drug if blood flow not limiting
Hepatic Drug Clearance

• For High Extraction Drugs:

• Equation reduces to simple form:

• ClH = Q
High Extraction Drugs/
Xenobiotics/ Endogenous Compounds

• Nitroglycerine
• Lidocaine
• Propranolol
• Bile Acids
Hepatic Drug Clearance

• For Low Extraction Drugs:

• Equation reduces to simple form:

• ClH = fx unbound x ClINT
Low Extraction Drugs/ Endogenous
Compounds

• Diazepam
• Phenytoin
• Theophylline
• Bilirubin
Phase 1 Biotransformation and
Phase 2 Conjugation in Liver

O Sugar
OH
OH

Glucuronyl
CYP transferase

ER ER

Phase 1 Phase 2
Oxidative Conjugation to polar ligand
reactions Glucuronyl transferases
CYP-mediated Sulfotransferases
Glutathione-S- transferases
Contributions of Specific P450s to
Drug Metabolism

CYP3A4
CYP3A4
CYP2E1

CYP2D6
CYP2C*

CYP1A2
unknown

* multiple subfamily
members exist
Role: Production of an active drug
Biotransformation of an inactive pro-drug) to an active drug

pro-drug

active drug

Glucuronyl
OH transferase

CYP3A4

ER ER
Phase 2: Conjugation

• Catalyze covalent binding of drugs to polar

ligands (“transferases”)
▫ glucuronic acid, sulfate, glutathione, amino acids
• Increase water solubility
• Enzymes generally in ER, some cytosolic
• Often follow Phase I biotransformation
reactions
▫ frequently use -OH or other group added by CYPs
Role: Production of less-toxic metabolite
Conjugation of acetaminophen to UDP-glucuronic acid

NH-CO-CH3

NH-CO-CH3
UDP
+ Glucuronic acid O Glucuronic acid

OH UDP-glucuronyl
transferase

ER
CYP

ER
Drug Elimination

Once drugs have been altered by Phase I and Phase II

enzymes, they may be excreted by:

• Biliary Excretion
• Renal Excretion
Common Theme
• Liver uses similar mechanisms to handle
endogenous and xenobiotic compounds
Drug-Drug Interactions:
Various Issues

• Competitive inhibition of CYP

▫ drug A increases toxicity of drug B
• Induction of CYP
▫ increased elimination of drug
▫ increased production of toxic metabolites
• Applicable to environmental and “natural”
products as well as drugs
 Cytochrome P450
Metabolism/Competition
B D
A C

CYP1A2 CYP2D6 CYP3A4

ENDOPLASMIC RETICULUM
Case Presentation
• 23 year old man underwent cardiac
transplantation.
• Begun on usual doses of cyclosporin A (6
mg/kg/day) and levels were therapeutic for 2
days.
• Also given ketoconazole for suspected fungal
infection.
• Then developed renal failure and seizures
consistent with acute cyclosporin A toxicity -
blood levels of CsA were high.
Case Continued
• Dose was reduced and therapeutic blood levels
were re-established
• However, 6 weeks after surgery his blood levels
had fallen to subtherapeutic levels and dose had
to be increased again.
• WHY?
Drug Interactions and CYP3A4

Absence of competition -

CYP3A4

Drug: Unaltered
Cyclosporin
Cyclosporin A

Cyclosporin
Metabolites
Cytochrome P450 Metabolism

A B CsA Keto

CYP1A2 CYP2D6 CYP3A4

ENDOPLASMIC RETICULUM
 Our Case: Subtherapeutic cyclosporin
levels 6 weeks after discharge

Ketoconazole

CYP3A4
Unaltered
Drug
Cyclosporin A
Cyclosporin A

Metabolites
Our Case
• Patient has Cyclosporin A toxicity and high blood
levels 2 days after transplant.
• Not likely due to genetically low levels of CYP3A4
as six weeks later his blood levels were low.
• More likely high levels due to simultaneous
administration of a competing drug - ketoconazole
for suspected fungal infection.
Induction of CYP Enzymes

• CYP substrates can induce CYP gene

transcription, increasing liver capacity for drug
metabolism.
• Induction is usually specific for one or only a few
CYPs.
• Induction likely occurs through broad-specificity
orphan nuclear receptors.
Approach to Drug-Drug Interactions

• Be aware of the problem

• Look up potential interactions
▫ computer databases
• Monitor blood levels of drug
• Monitor biologic action
• Monitor for known toxicities
Effects of Drugs on the Liver:
Drug-Induced Liver Disease

• Many types of injury

• Some predictable
▫ drug-drug interactions
• Most rare and not easily predictable
▫ idiosyncratic/metabolic/genetic
• Therapeutic misadventure
Drug-Induced Liver Injury

• Hepatocellular injury
▫ toxic metabolite: isoniazid, acetaminophen
• Autoimmune hepatocellular injury
▫ halothane hepatitis
• Cholestatic liver injury
▫ estrogen
DILI Incidence
• 10 fold increase in No. of reported cases between 1964-
1973 in Japan

• 10% of cases of hepatitis in a major hepatology center in

France

• 20% of instances of jaundice among geriatric population

in USA

• 9% of hospitalized patients with AST ≥ 400 IU/L in a

survey in UK

• 25%-40% of fulminent hepatic failure

DILI:
• Predictable
▫ Dose related
▫ Intrinsically hepatotoxic drugs
▫ Acute (hours)
▫ Injury pattern is usually necrosis
▫ Clinically → Fulminant (Acute Hepatitis)
▫ Example: Acetaminophine

• Unpredictable
▫ Not dose related
▫ Rare 0.01-1.0 %
▫ Weeks to months after ingestion of drug
▫ Idiosyncratic
 Immune mediated idiosyncrasy (Hypersensitivity)
 Rash
 Fever
 Arthragia
 Eosinophilia
 Example: Phenytoin, Sulfonamides, Valproate

 Metabolic idiosyncrasy (Production of toxic metabolites)

 Example: INH, Ketoconazole, and Diclofenac
Diagnosis of DILI

• High index of suspicion

• Abnormalities in hepatic associated enzymes
• Hepatitis like symptoms
• Jaundice
• Drug history
▫ Dose
▫ Duration of therapy
▫ Time between initiating therapy and the development of hepatic injury
(latency)
• Exclusion of other causes of liver diseases 2%-5% of
▫ Hepatitis B
general
▫ Hepatitis C
population
▫ Alcoholic liver diseases
▫ Non alcoholic fatty liver diseases
▫ Hemochromatosis
Diagnosis of DILI

Extrahepatic manifestations

▫ Hypersensitivity reactions
 Fever
 Rash
 Arthralgias
 Esinophelia

▫ Unique clinical syndromes

Risk Factors For Susceptibility to DILI

• Methotrexate • Acetaminophen
▫ Alcohol ▫ Alcohol
▫ Obesity ▫ Fasting
▫ D.M ▫ INH
▫ Chronic hepatitis
• Valproate
• INH ▫ Young age
▫ HBV,HCV,HIV ▫ Anticonvulsants
▫ Alcohol
▫ Older age • Diclofenac
▫ Female ▫ Female
▫ Osteoarthritis
Risk Factors For Susceptibility to DILI

• Sulfonamide • Rifampicin
▫ HIV ▫ Slow acetylators
▫ Slow acetylator ▫ INH
▫ Genetic defect in defense
• Pyrazinamide
• Anticonvulsats ▫ Slow acetylators
▫ Genetic defect in ▫ INH
detoxification
Acetaminophen Metabolism
Glucuronidation
Sulfation
Acetaminophen Stable
Excretion
Metabolites

CYP2E1 Glutathione
(CYP3A4, CYP1A2) conjugation

Toxic metabolites (NAPQI)

Covalent binding
oxidative stress

Hepatocyte damage
Acetaminophen Metabolism:
High Dose
Glucuronidation
Acetaminophen Sulfation
Stable
Overdose Saturated Metabolites
Excretion

Glutathione
CYP2E1 conjugation

Toxic metabolites (NAPQI)

N-acetylcysteine
Covalent binding (antidote to overdose)
oxidative stress

Hepatocyte damage
Therapeutic Misadventure

• Patient uses a drug at a “safe” dose.

• In the presence of an environmental change,

toxicity develops.

• Example: acetaminophen and alcohol

Drug-Induced Liver Disease:
Case
47 year old known alcoholic admitted through ER with
jaundice and disorientation.
1 week ago he developed abdominal pain, he thought this was
due to alcohol so stopped drinking.
Took over-the-counter pain reliever for several days and
abdominal pain subsided.
Labs: Bilirubin 5.7 mg/dl
Alk Phos 210 IU/l
AST 10,310 IU/l
ALT 12,308 IU/l
PT 41 seconds
What type of liver problem does he have?
Acetaminophen Metabolism
Glucuronidation
Sulfation
Acetaminophen Stable
Excretion
Metabolites

CYP2E1 Glutathione
(CYP3A4, CYP1A2) conjugation

Toxic metabolites (NAPQI)

Covalent binding
oxidative stress

Hepatocyte damage
A Potentially Lethal
Combination

Andy Melton, Flickr Jerry Lai, Flickr

Acetaminophen Metabolism After
Chronic EtOH Use and with Fasting
Glucuronidation
Sulfation
Stable
Acetaminophen Metabolites
Excretion

CYP2E1 Glutathione
conjugation

Toxic metabolites (NAPQI)

EtOH
Fasting
Covalent binding
oxidative stress

Hepatocyte damage
Drugs that Induce CYP2E1

• Isoniazid (INH)
• Phenobarbital
• Ethanol !!!
Approach to Drug-Induced Liver
Disease

• Always consider drugs/herbs/toxins in the

differential diagnosis of ALL liver
diseases
• Stop all drugs/agents immediately
• Look it up - check computer databases
and textbooks
Approach to Prevention of Drug-
Induced Liver Disease
• Be aware of problem and check databases for
known interactions
• Screen for initial mild liver damage before it
becomes severe - AST/ALT most used
• Holy Grail: tailor drugs to patient’s
genetic/environmental/drug profile
Approach to Drug Use in Patients
with Significant Liver Dysfunction

• Monitor the biologic effect of the drug

(heart rate)
• Monitor blood levels (if possible)
• Start with low dose and titrate up to
biologic effect or blood level
 Regulatory actions due to DILI (1995-2006)
Withdrawals Second Line Warnings
bromfenac felbamate Acetaminophen
troglitazone leflunomide
tolcapone
nefazodone
pemoline trovafloxacin Nevirapine
pyrazinamide/rifampin
terbinafine
valproic acid
zifirlukast
atomoxetine
interferon 1b –1b and 1a
saquinavir
infliximab
bosentan
telithromycin
http://www.fda.gov/medwatch/safety.htm (kava, lipokinex)
Of the 23 drugs that have
undergone withdrawal, restriction
or warnings

19/23 (82%) were associated with acute

idiosyncratic hepatocellular injury
Prescription of DILI to patients with
liver disease
Prescription of DILI to patients with
liver disease

If necessary , need special treatments:

1. Dose adjustment
2. Administration of other compounds
Prescription of DILI to patients with
liver disease in a Public Hospital in
Tasikmalaya 2010-2011 (52 patients)
Prescription of DILI to patients with
liver disease in a Public Hospital in
Bekasi 2010-2011 (69 patients)
Prescription of DILI to patients with liver
disease in a Private Hospital in Eastern
Bandung 2010-2011 (153 patients)
Prescription of DILI to patients with liver
disease in a Private Hospital in Northern
Bandung 2010-2011 (103 patients)
Community
Clinical Pharmacist